The mammalian neurokinins are peptide neurotransmitters found in the peripheral and central nervous systems. The three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). N-terminally extended forms of at least NKA are known. Three receptor types are known for the principal neurokinins. Based upon their relative selectivities for the neurokinins SP, NKA and NKB, the receptors are classified as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors, respectively. In the periphery, SP and NKA are localized in C-afferent sensory neurons, which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers. C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics. The effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation, increased mucus secretion and activation of mast cells. Neurokinin antagonists that interact with NK1, NK2 and NK3 receptors, having different chemical structures have been described. Particularly international publications WO 98/07722, WO 96/39383 and WO 98/25617, and regional publications EP 428434, EP 474561, EP 515240 and EP 559538 disclose the preparation of a variety of chemical structures.
NK1activity is also implicated in depression and anxiety, mice with genetically altered NK1 receptors have decreased anxiety related behavior (Santarelli, L., et. al., Proc. Nat. Acad. Sci. (2001), 98, 1912) and NK1 antagonists have been reported to be effective in an animal model of depression (Papp, M., et. al., Behav. Brain Res. (2000), 115, 19).
Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used for the treatment of major depressive disorder (MDD) and are considered well-tolerated and easily administered. SSRIs, however, have a delayed onset of action, are associated with undesirable side effects, such sexual dysfunction, and are ineffective in perhaps 30% of patients (M. J. Gitlin, M J, J. Clin. Psych., 55, 406-413, 1994).
Compounds with dual action as NK1 antagonists and serotonin reuptake inhibitors may also provide a new class of antidepressants. Indeed, compounds combining NK1 antagonism and serotonin reuptake inhibition have been described (Ryckmans, T., et. al, Bioorg. Med. Chem. Lett. (2002), 12, 261).